In cancer chemotherapy, attempts have been made to develop a DDS to improve specificity; however, almost none of these attempts focus on the tumor environment. Specifically, tumor tissues are in a special environment having a pH (a pH around 6.5) lower than that of physiological conditions (a pH around 7.4). However, drug delivery carriers that act in a tumor tissue-specific manner in such a way as to respond to this small pH change have yet to be developed. Until now, in anticipation of the EPR effect (Enhanced Permeation and Retention effect), polyethylene glycol (PEG), which is a hydrophilic macromolecule, has been used to modify the surface of liposomes, etc., and the modified liposomes have been used as a carrier of, for example, anticancer drugs (e.g., Patent Literature (PTL) 1). However, drug release from such a PEG-modified carrier after delivery to tumor tissues is rate-limiting, and the drug cannot be effectively released in the tumor tissues. The peptide-liposome complex disclosed in PTL 2 retains a positive charge due to the presence of basic amino acid (lysine or arginine) at the N-terminal region, and a change in charge does not occur depending on pH; sufficient blood-circulating properties can thus not be expected.
Non-Patent Literature (NPL) 1 uses His segments as a pH-responsive region. According to the technique disclosed in NPL 1, a drastic decrease in the pH of the external environment from 7.4 to 5.0 causes a neutral His to be positively charged, and the thus-increased electrostatic repulsion causes disruption of micelles. However, a His would not sufficiently be protonated alone at a weakly acidic pH of 6.5; therefore, causing charge reversal is difficult. For this reason, drug release associated with the disruption of micelles at a pH of 6.5 cannot be expected.
NPL 2 discloses pH-responsive micelles whose surface charge changes from negative to positive when dimethylmaleic acid chemically bonded to a lysine segment at a terminal of a block polymer is dissociated due to a decrease in pH. In the peptide disclosed in NPL 2, dissociation of the dimethylmaleic acid causes exposure of positively charged lysine residues; even if the pH is increased, such a state does not return to the original state.